Shock : molecular, cellular, and systemic pathobiological aspects and therapeutic approaches : the official journal the Shock Society, the European Shock Society, the Brazilian Shock Society, the International Federation of Shock Societies
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Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a nuclear receptor that regulates diverse biological functions including inflammation. The PPARgamma ligands have been reported to exert cardioprotective effects and attenuate myocardial reperfusion injury. Here, we examined the molecular mechanisms of their anti-inflammatory effects. ⋯ The cardioprotection afforded by ciglitazone was attenuated by the PPAR-gamma antagonist GW-9662. In contrast, GW-9662 did not affect the beneficial effects afforded by 15d-PGJ2. Thus, our data suggest that treatment with these chemically unrelated PPAR-gamma ligands results in diverse anti-inflammatory mechanisms.
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Randomized Controlled Trial
Glibenclamide dose response in patients with septic shock: effects on norepinephrine requirements, cardiopulmonary performance, and global oxygen transport.
Adenosine triphosphate-sensitive potassium channels are important regulators of arterial vascular smooth muscle tone and are implicated in the pathophysiology of catecholamine tachyphylaxis in septic shock. The present study was designed as a prospective, randomized, double-blinded, clinical pilot study to determine whether different doses of glibenclamide have any effects on norepinephrine requirements, cardiopulmonary hemodynamics, and global oxygen transport in patients with septic shock. We enrolled 30 patients with septic shock requiring invasive hemodynamic monitoring and norepinephrine infusion of 0.5 microg.kg-1.min-1 or greater to maintain MAP between 65 and 75 mmHg. ⋯ Glibenclamide decreased plasma glucose concentrations in a dose-dependent manner but failed to reduce norepinephrine requirements. None of the doses had any effects on cardiopulmonary hemodynamics, global oxygen transport, gas exchange, or electrolytes. These data suggest that oral glibenclamide in doses from 10 to 30 mg fails to counteract arterial hypotension and thus to reduce norepinephrine requirements in catecholamine-dependent human septic shock.
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Comparative Study
Norepinephrine and intestinal mucosal perfusion in vasodilatory shock after cardiac surgery.
Patients with norepinephrine-dependent vasodilatory shock after cardiac surgery (n = 10) were compared with uncomplicated postcardiac surgery patients (n = 10) with respect to jejunal mucosal perfusion, gastric-arterial PCO2 gradient, and splanchnic oxygen demand/supply relationship. Furthermore, the effects of norepinephrine-induced variations in MAP on these variables were evaluated in vasodilatory shock. Norepinephrine infusion rate was randomly and sequentially titrated to target MAPs of 60, 75, and 90 mmHg (0.25 +/- 0.24, 0.37 +/- 0.21, and 0.55 +/- 0.39 microg/kg per minute, respectively). ⋯ Jejunal mucosal perfusion, jejunal mucosal hematocrit, RBC velocity, gastric-arterial mucosal PCO2 gradient, splanchnic oxygen extraction, and splanchnic lactate extraction were not affected by increasing infusion rates of norepinephrine. In patients with norepinephrine-dependent vasodilatory shock after cardiac surgery, intestinal mucosal perfusion was higher, whereas splanchnic and gastric oxygen demand/supply relationships were impaired compared with postoperative controls, suggesting that intestinal mucosal perfusion is prioritized in vasodilatory shock. Increasing MAP from 60 to 90 mmHg with norepinephrine in clinical vasodilatory shock does not affect intestinal mucosal perfusion and gastric or global splanchnic oxygen demand/supply relationships.
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Depressed heart rate variability (HRV) in septic patients is known to be associated with poor outcome. However, neither etiology of depression of HRV nor its clinical significance has been clearly determined. Because hypercytokinemia plays an important role in sepsis, we investigated the relationships between depressed HRV and IL-6 blood level. ⋯ These findings indicate that reduction in HRV indices is associated with hypercytokinemia, indicating that the autonomic nervous system and the inflammatory response mediated by the cytokine network affect each other. These results also suggest that depression of HRV is closely related to rapid changes in blood pressure. Thus, heart rate variability indices are associated with both the severity and poor outcome of sepsis.
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The development of sepsis and multiple organ failure are important determinants of the outcome in critically ill patients. Hepatosplanchnic hypoperfusion and resulting intestinal and hepatic cell damage have been implicated as central events in the development of sepsis and multiple organ failure. Our aim was to study (1) the relation between intramucosal perfusion and intestinal and hepatic cell damage in an early phase of sepsis and (2) the correlation of these parameters with mortality. ⋯ At intensive care unit admission, nonsurvivors had significantly higher I-FABP and L-FABP values than survivors (I-FABP: 325 vs. 76 pg/mL, P < 0.04; L-FABP: 104 vs. 31 ng/mL, P < 0.04). Patients with abdominal sepsis was especially responsible for high-admission I-FABP and L-FABP levels in nonsurvivors (I-FABP: 405 vs. 85 pg/mL, P < 0.04; L-FABP: 121 vs. 59 ng/mL, P < 0.04). This study shows that splanchnic hypoperfusion correlates with intestinal mucosal damage, and that elevated plasma levels of I-FABP and L-FABP are associated with a poor outcome in critically ill patients with abdominal sepsis.